A novel nasal booster approach could help bridge the gap between systemic vaccination and infection-blocking mucosal immunity, providing new insights into next-generation coronavirus vaccine strategies.

study: Intranasal booster promotes memory B cell class switching and homing for mucosal IgA responses. Image credit: Jo Panuwat D / Shutterstock

Although current intramuscular vaccines are good at inducing blood-based immunity, they may not be able to prevent SARS-CoV-2 infection, and this discrepancy is due to their inability to elicit a response in the upper respiratory mucosa. However, in this study, we evaluated the immune response rather than the outcome of clinical infection.

In a recent study published in the journal JCI Insightsresearchers found that intranasal (in) Boosters may increase efficacy of Previous intramuscular COVID-19 vaccine (inactivated whole virus) in small human cohorts. Paired antibody analysis in 6 volunteers, cytokine analysis in 8 volunteers, and detailed monoclonal antibody and multi-omics analysis primarily derived from a single donor were performed.

The study results demonstrated that a two-dose IN (Ad5-S-Omicron vaccine) “reprograms” existing immune memory from previous injections and causes a specialized “class switch” to the secretory type. IgA (Shiga)antibody.

Encouragingly, these novel nasal antibodies were observed to be substantially, in some cases hundreds of times more effective at neutralizing omicron variants than standard blood antibodies. This study provides preliminary mechanistic insights relevant to next-generation mucosal vaccines by identifying molecular signatures consistent with mucosal homing rather than directly tracking cell migration.

The mucosal immune gap and the biology of secretory IgA

Since the beginning of the COVID-19 pandemic, one of the main objectives of early vaccination programs has been to reduce severe illness and hospitalizations, especially at a time when health care capacity is stretched. Early coronavirus vaccines were administered intramuscularly (I) Injection. These were aimed at preventing hospitalization by reducing the risk of severe lower respiratory tract disease, rather than directly targeting lung tissue.

However, subsequent studies found that these vaccines provided more limited mucosal protection in the nasal and throat cavities, the main points of entry for SARS-CoV-2. This “entry point gap” helped explain why fully vaccinated people often develop infections.

Recent research has identified secretory IgA (sIgA) as a potential breakthrough in protecting the nose and throat against COVID-19. In contrast to blood-derived single-unit antibodies, sIgA is a dimeric (two-part) structure specifically designed to live and function on mucosal surfaces, acting as a molecular “gatekeeper,” capturing and neutralizing pathogens before they can attach to epithelial cells.

Unfortunately, the human cellular mechanisms that recruit anti-SARS-CoV-2 antibodies to the nasal cavity are still not fully understood.

Study design and multiomic immune profiling

This study aimed to address this knowledge gap by investigating whether nasal booster vaccination can augment the effectiveness of intramuscular vaccination in protecting individuals from future infections, and the mechanisms underpinning the recruitment of sIgA to the nasal cavity, recognizing that clinical prevention outcomes have not been directly measured.

The study sample consisted of multiple small subgroups. Generalizability was limited because paired antibody potency analysis included 6 participants, cytokine profiling 8 participants, and focused monoclonal antibody discovery primarily from a single donor. Study participants received two intranasal boosters with the Ad5-S-Omicron vaccine, an adenovirus-based platform encoding the spike protein of the Omicron BA.1 variant.

The study leveraged next-generation “multi-omics” techniques to monitor participants’ immune responses. These include:

• Mass spectrometry of immunoglobulin sequences (MS Ig-seq). A liquid chromatography and tandem mass spectrometry-based approach used to identify specific antibody proteins in nasal washes.
• Single-cell B-cell receptor sequencing (scBCR-seq) is a high-throughput method that allows genetic characterization of B cells responsible for antibodies identified with MS Ig-seq.
• Single-cell RNA-seq (scRNA-seq), high-throughput gene expression profiles of B cells at multiple time points (days 10 and 30). Observe when and how B cells move into the nasal cavity. It is mainly inferred from receptor expression patterns rather than directly. in vivo tracking.
• In this study, we used cytokine assays to measure the concentrations of 15 signaling proteins in nasal swabs to characterize the chemical environment that recruits immune cells to the respiratory lining.

Enhancement of sIgA efficacy and immune reprogramming

Research results have revealed that there are significant differences between nasal immunity and blood immunity. Purified nasal sIgA was observed to be significantly (many times) more potent than serum IgG found in the same individuals.

Specifically, nasal sIgA was 17-fold more potent against wild-type virus, 30-fold more potent against BA.1, 125-fold more potent against BA.5, and 813-fold more potent against the XBB.1.5 mutant.

Through analysis of multi-omics data, they were able to track the “reprogramming” of the participants’ immune systems. Key findings include:

• Memory restimulation: Intranasal boosters were observed to not only stimulate the production of new immune cells, but also restimulate the “memory” B cells created to secrete antibodies by the initial needle injection.
• Antibody class switch: Remarkably, these restimulated B cells underwent class switch recombination (CSR), shifts from IgG to IgA production. The probability of this switch increased to approximately 70.8% after nasal booster administration in clonotype-level analyzes rather than in cohort-wide estimates.
• Gene upregulation: B cell homing receptors, particularly CCR10 (chemokine receptor 10) and α4β1 (integrin α-4β-1), were found to be significantly upregulated after intranasal booster administration.
• Upregulation of cytokines: In this study, we observed a transient increase in cytokines such as CCL27 and CCL28 (p < 0.05 or p < 0.01), which served as targets for homing receptors on the surface of IgA-secreting cells, thereby signaling these B cells to congregate in the nose, although the responsible migration pathway remains incompletely defined.

Clinical implications and durability considerations

Although this study is small and partially from a single-donor analysis, it provides preliminary human evidence that a “prime-boost” strategy of boosting a previous intramuscular vaccine with an intranasally administered adenovirus-based platform enables multisystem protection from the point of entry (sIgA-based mucosal protection) to the lung (IgG-based hemoprotection), although clinical efficacy and durability require confirmation in larger trials.

In this study, nasal sIgA levels were observed to decline over time (65% reduction within 3 months), suggesting that regular mucosal boosters may be necessary to maintain immunity. However, the real-world conservation implications remain uncertain.